Over 250 million cases of malaria are reported each year, 1 million of which result in death. Currently, no drugs are universally successful in treating malaria due to widespread drug resistance; new antimalarials are desperately needed. Chloroquine and artemisinin, two of the most effective and widely used antimalarial drugs, are derived from plants. It is likely that plants harbor many more potent and as yet undiscovered antimalarial compounds. A massive antimalarial screening program conducted by Merck during the Second World War (Spencer et al 1947) provides a valuable source of preliminary antimalarial plant information. Eighty eight species (out of 600 tested) were proven active against avian strains of malaria in that study, but nearly half (39) have been neglected in subsequent studies. These plants represent promising leads for further antimalarial inquiry. Our preliminary research has confirmed the activity of 5 of 6 species identified as active by Merck, validating the proposed follow up of this work. The work outlined in this application evaluate the understudied, but promising antimalarial plants identified by Merck's scientists in 1947 using a combination of modern in vitro assay for inhibition of Plasmodium falciparum proliferation in cultured erythrocytes and follow-up in vivo animal studies. State-of-the- art chemical isolation and characterization techniques will be applied to compare and elucidate the composition, chemical identity, and bioactivity of fractions and compounds from antimalarial plant extracts with the highest in vitro activity and low toxicity. These substances will be tested in animal model of malaria using C57Bl mice infected with the Plasmodium berghei strain. This model will also allow synergistic and pharmacodynamic investigations of promising extracts. The relevance of this research application to public health is to support the traditional use of plants used to treat malaria, provide crucial preclinical data for future development of novel antimalarial therapies, and help to elucidate novel biochemical and physiological information about plasmodium-host interactions. By evaluating botanical treatments that might be cultivated locally, used locally, and have local benefits, this scientific work will have broad and long-term impacts both on the global scale as well on the communal scale in the fight against malaria.